The predictivity of the toxicity of pharmaceuticals in humans from animal data — an interim assessment

Olson, Harry M.; Betton, Graham; Stritar, Jeffrey A.; Robinson, Denise E.

doi:10.1016/s0378-4274(98)00261-6

Cited by 73 publications

(41 citation statements)

References 4 publications

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“…After removal of structural outliers using an implementation of the applicability domain, an accuracy of 67.8% was obtained for the reduced set of 222 compounds. This study confirmed low cross-species concordance of liver effects (40 --45%), which is in agreement with previous investigations [36,97]. On the other hand, it showed the reasonably good predictivity of cheminformatics techniques using data generated by automated text mining with limited manual curation.…”

Section: 2supporting

confidence: 92%

In silicomodels for drug-induced liver injury – current status

Przybylak

Cronin

2012

Expert Opinion on Drug Metabolism & Toxicology

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Most of the predictive methods discussed in this review are based on the structural properties of chemicals and do not take into account genetic and environmental factors; therefore, their predictions are still uncertain. To improve the predictability of in silico models for DILI, it is essential to better understand its mechanisms as well as to develop sensitive toxicogenomics biomarkers, which show relatively good differentiation between hepatotoxins and non-hepatotoxins.

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Section: 2supporting

confidence: 92%

In silicomodels for drug-induced liver injury – current status

Przybylak

Cronin

2012

Expert Opinion on Drug Metabolism & Toxicology

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“…Human hepatotoxicity, as well as hypersensitivity and cutaneous reactions, are particularly difficult to identify during regulatory-based animal studies. Only 50% of drugs found to be hepatotoxic in clinical studies showed concordance with animal toxicity results (39,40). In addition, there are profound ethical issues associated with the widespread use of animals for this purpose.…”

Section: High-content Toxicologymentioning

confidence: 93%

De-Risking Drug Discovery Programmes Early with ADMET

Tsaioun¹,

Kates²

2011

Drug Discovery and Development - Present and Future

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“…In This has been shown in a study of 131 pharmaceutical agents that addition, for drugs used topically, acute phototoxicity can be showed toxic effects in humans, an outcome that was only predictinvestigated using a human 3-dimensonal skin model that overed in 69% of the animal toxicity studies. [68] comes some limitations of the 3T3 assays, in particular the fairly It is not surprising, therefore, that primary cell cultures or cell low UV tolerance and inability to model the bioavailability of lines derived from the major target organs of toxicity are used for dermally-applied compounds. [63] toxicity studies.…”

Section: A High Fraction Of Test Compounds Show An Effect On the Hergmentioning

confidence: 99%

Improving Decision-Making in Drug Development Using In Vitro Toxicology Screening

Suter

2007

International Journal of Pharmaceutical Medicine

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areas of pharmaceutical safety evaluations: genetic toxicology, safety pharmacology, phototoxicity and organ toxicity. Since in vitro screening and mechanistic in vitro investigations provide early information on toxicity, the safety of patients in clinical studies has been significantly improved by the performance of in vitro studies. In addition, the high throughput of in vitro technologies allows the pharmaceutical industry to eliminate toxic structures long before 'first dose in human' studies. In vitro organ toxicity models provide important mechanistic information. However, a comprehensive analysis of the predictivity of genetic toxicity tests for rodent carcinogenicity has revealed a major problem with the specificity of the in vitro mammalian cell assays, leading to a risk that the development of efficacious drug candidates might have been stopped because of false-positive in vitro results. Therefore, data from in vitro studies, including the recently introduced human ether-a-go-gorelated gene (hERG) potassium channel inhibition test to predict QT interval prolongation and the in vitro 3T3 neutral red uptake (3T3 NRU) phototoxicity test to predict phototoxicity, should be used with great care for decision-making. All areas of in vitro safety assessments require significant refinements. Stem cell-derived cell lines and the use of 'omics' technologies are expected to make a major contribution to an improved future generation of in vitro screening assays.

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The predictivity of the toxicity of pharmaceuticals in humans from animal data — an interim assessment

Cited by 73 publications

References 4 publications

In silicomodels for drug-induced liver injury – current status

In silicomodels for drug-induced liver injury – current status

De-Risking Drug Discovery Programmes Early with ADMET

Improving Decision-Making in Drug Development Using In Vitro Toxicology Screening

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